SAT077 Association Of Mitochondrial DNA With Type-2-diabetes, Glucose Level, And Insulin Resistance

Abstract

Abstract Disclosure: M. Heydarpour: None. L. Pojoga: None. J.R. Romero: None. G.H. Williams: None. J.S. Williams: None. Background: Mitochondrial dysfunction leads to decreased Adenosine-3-phosphate (ATP) production and increased ROS production, leading to insulin resistance, and diabetes (T2D). Mutations in mitochondrial DNA (mtDNA) have been associated with increased ROS production. Current studies have shown a role for mtDNA variants in the pathogenesis of both T2D and insulin resistance. Despite both of these disorders are controlled by many features involving interplay between genetic and environmental factors, however amongst genetic factors, variations in mtDNA have shown a potential role in the risk of T2D. We analyzed the genomic influence of mtDNA on T2D, insulin resistance, and fasting plasma glucose in humans. Methods: Participants (113 cases with T2D and 303 controls) from the HyperPATH Cohort were selected and genotyped using a Multi-Ethnic-Genotyping-Array. Individuals consumed two study diets containing high (>200mEq/day) and low (<10mEq/day) sodium content for 7 days each. The Homeostasis Model Assessment (HOMA-IR) index was used to assess insulin resistance. We performed association analyses between 275 mitochondrial genetic markers (SNVs) and three outcomes (T2D, insulin resistance, and fasting plasma glucose) using PLINK program. Results: We identified 2 significant SNVs within mtDNA that associated with T2D after adjusting the model for sex, age, study site, and BMI. One SNV (rs2248727, OR=3.15, P=0.00035) was within the coding region of Cytochrome C Oxidase III (COX3) and another (rs2857284, OR=3.13, P=0.00037) within the coding region of NADH Dehydrogenase subunit 4 (ND4). Further, we identified 2 SNVs associated with fasting plasma glucose; rs28359176, beta=22.7, P=0.0006 in the coding region of NADH Dehydrogenase subunit 5 (ND5), and rs367951226 beta=22.7, P=0.0006) in the region of ATP Synthase membrane subunit 6 (ATP6). We also identified a significant signal (rs376888742, beta=5.61, P=6.09E-06) associated with insulin-resistance in the coding region of Cytochrome B (CYB). Conclusion: These results show a significant association between mitochondrial ND4 and COX3 gene variants with T2D and CYP with insulin resistance. Gene variants of mitochondrial ND5 and ATP6 were associated with increase plasma glucose. Presentation: Saturday, June 17, 2023